COMMISSION REGULATION (EC) No 1085/2003 of 3 …...Articles 15(4) and 37(4) thereof, Whereas: (1) In the light of practical experience in the application of Commission Regulation (EC)

L 159/24 EN 27.6.2003Official Journal of the European Union

COMMISSION REGULATION (EC) No 1085/2003

of 3 June 2003

concerning the examination of variations to the terms of a marketing authorisation for medicinalproducts for human use and veterinary medicinal products falling within the scope of Council

Regulation (EEC) No 2309/93

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European Com-munity,

Having regard to Council Regulation (EEC) No 2309/93 of22 July 1993 laying down Community procedures for theauthorisation and supervision of medicinal products forhuman and veterinary use and establishing a European Agencyfor the Evaluation of Medicinal Products (1), as amended byCommission Regulation (EC) No 649/98 (2) and in particularArticles 15(4) and 37(4) thereof,

Whereas:

(1) In the light of practical experience in the application ofCommission Regulation (EC) No 542/95 of 10 March1995 concerning the examination of variations to theterms of a marketing authorisation falling within thescope of Council Regulation (EEC) No 2309/93 (3), asamended by Regulation (EC) No 1069/98 (4), it isappropriate to simplify the procedure for varying theterms of a marketing authorisation.

(2) Due to the technical adaptation of Annex I to Directive2001/83/EC of the European Parliament and of theCouncil of 6 November 2001 on the Community coderelated to medicinal products for human use (5), it isappropriate to introduce in this Regulation provisionson variations related to plasma master files and vaccineantigen master files.

(3) Some of the procedures laid down in Regulation (EC)No 542/95 should therefore be adjusted but withoutdeparting from the general principles on which thoseprocedures are based.

(1) OJ L 214, 24. 8.1993, p. 1.(2) OJ L 88, 24.3.1998, p. 7.(3) OJ L 55, 11.3.1995, p. 15.(4) OJ L 153, 27.5.1998, p. 11.(5) OJ L 311, 28.11.2001, p. 67.

(4) It is appropriate to provide for a simplified and rapidnotification procedure to enable the introduction ofcertain minor changes, which do not affect the approvedquality, safety or efficacy of the product, without priorevaluation by the European Agency for the evaluationof medicinal products (hereinafter referred to as ‘theAgency’). However, for other types of minor variationsevaluation of the submitted documentation by theAgency should still be required.

(5) The various types of minor variation should be classifiedin order to determine the procedure to follow; it isparticularly necessary to give a precise definition of thetype of minor variation for which no prior evaluation isneeded.

(6) It is necessary to clarify the definition of an ‘extension’to a marketing authorisation, although it should still bepossible to submit a separate, full application formarketing authorisation for a medicinal product whichhas already been authorised but under a different nameand with summary of product characteristics.

(7) It is appropriate to allow the Agency to reduce theevaluation period in urgent cases or to extend it in thecase of a major variation entailing important changes.

(8) It is necessary to simplify the administrative proceduresfor minor variations regarding the updating of marketingauthorisations by allowing the Commission to groupthese updates every six months in one single decision.

(9) The time-frame for the procedure to be followed wherethe Commission imposes urgent safety restrictionsshould be clarified.

27.6.2003 EN L 159/25Official Journal of the European Union

(10) Further clarification should be introduced as regardsrevision of the labelling, the package leaflet/insert or thesummary of product characteristics; nevertheless theprocedures laid down in this Regulation should notapply to changes to the labelling or to the packageleaflet/insert which are not consequential to changes tothe summary of product characteristics.

(11) For the sake of clarity, it is appropriate to replaceRegulation (EC) No 542/95.

(12) The measures provided for in this Regulation are inaccordance with the opinion of the Standing Committeeon Medicinal products for Human Use and the StandingCommittee on Veterinary Medicinal Products,

HAS ADOPTED THIS REGULATION:

Article 1

Subject matter

1. This Regulation lays down the procedure for the examin-ation of applications for variations to the terms of a marketingauthorisation granted in accordance with Regulation (EEC)No 2309/93.

2. This Regulation also applies for the examination ofapplications of variations to the terms of a plasma master fileand of a vaccine antigen master file, as defined in Annex I ofDirective 2001/83/EC.

Article 2

Scope

This Regulation shall not apply to:

(a) extensions of marketing authorisations which fulfil theconditions set out in Annex II to this Regulation;

(b) transfers of a marketing authorisation to a new holder;

(c) changes to the maximum residue limit as defined inArticle 1(1)(b) of Council Regulation (EEC) No 2377/90 (1).

The extension referred to in point (a) of the first paragraphshall be evaluated in accordance with the procedures set out inArticles 6 to 10 and Articles 28 to 32 of Regulation (EEC)No 2309/93 for medicinal products for human use andveterinary medicinal products, respectively.

Article 3

Definitions

For the purposes of this Regulation, the following definitionsshall apply:

(1) OJ L 224, 18.8.1990, p. 1.

1. ‘variation to the terms of a marketing authorisation’means an amendment to the contents of the documentsreferred to in Article 6(1) and (2) or Article 28(1) and (2)of Regulation (EEC) No 2309/93, such as they existed atthe moment the decision on the marketing authorisationwas adopted, in accordance with Article 10 or Article 32of that Regulation or after approval of any previousvariations;

2. a ‘minor variation’ of type IA or type IB means a variationlisted in Annex I which fulfils the conditions set outtherein;

3. a ‘major variation’ of type II means a variation that cannotbe deemed to be a minor variation or an extension of themarketing authorisation;

4. ‘urgent safety restriction’ means an interim change, dueto new information having a bearing on the safe useof the medicinal product, to the product informationconcerning particularly one or more of the followingitems in the summary of product characteristics: theindications, posology, contraindications, warnings, targetspecies and withdrawal periods.

Article 4

Notification procedure for minor variations type IA

1. With regard to minor variations of type IA, the marketingauthorisation holder (hereinafter referred to as ‘the holder’)shall submit to the Agency a notification accompanied by

(a) all necessary documents including those amended as aresult of the variation;

(b) the relevant fee provided for in Council Regulation (EC)No 297/95 (2).

2. A notification shall only concern one type IA variation.Where several type IA variations are to be made to the termsof a single marketing authorisation, a separate notificationshall be submitted in respect of each type IA variation sought;each such notification shall also contain a reference to theother notifications.

3. By way of derogation from paragraph 2, where a type IAvariation to the marketing authorisation leads to consequentialtype IA variations, a single notification may cover all suchconsequential variations. The single notification shall containa description of the relation between these consequentialtype IA variations.

4. Where a variation requires consequential revision of thesummary of product characteristics, labelling and packageleaflet/insert, this is considered as part of the variation.

(2) OJ L 35, 15.2.1995, p. 1.


5. If the notification fulfils the requirements set out inparagraphs 1 to 4, the Agency shall, within 14 days followingreceipt of the notification, acknowledge the validity of thisnotification and shall inform the holder accordingly.

The Agency shall, where appropriate, disseminate the amendeddocuments referred to in Article 3(1).

The Commission shall, where necessary and based on aproposal prepared by the Agency, update every six months themarketing authorisation which has been granted pursuant toArticle 10 or Article 32 of Regulation (EEC) No 2309/93.

The updated marketing authorisation shall be notified by theCommission to the holder.

The Community Register of Medicinal Products provided forin Articles 12 and 34 of Regulation (EEC) No 2309/93 shallbe updated as necessary.

Article 5

Notification procedure for minor variations type IB

1. With regard to minor variations of type IB, the holdershall submit to the Agency a notification accompanied by:

(a) all necessary documents demonstrating that the con-ditions laid down in Annex I for the requested variationare met, including all documents amended as a result ofthe application;

(b) the relevant fee provided for in Regulation (EC) No 297/95.

2. A notification shall only concern one type IB variation.Where several type IB variations are to be made to asingle marketing authorisation, a separate notification shall besubmitted in respect of each type IB variation sought; eachsuch notification shall also contain a reference to the othernotifications.

3. By way of derogation from paragraph 2, where a type IBvariation to the marketing authorisation leads to consequentialtype IA or type IB variations, a single type IB notification maycover all such consequential variations. The single applicationshall contain a description of the relation between theseconsequential type I variations.


5. If the notification fulfils the requirements set out inparagraphs 1 to 4, the Agency shall acknowledge receipt of avalid notification and shall start the procedure set out inparagraphs 6 to 10.

6. If, within 30 days of the date of the acknowledgement ofreceipt of a valid notification the Agency has not sent theholder its opinion provided for in paragraph 8, the variationapplied for shall be deemed to have been accepted.

The Agency shall inform the holder accordingly.

The Agency shall, where appropriate, disseminate the amendeddocuments referred to in Article 3(1).

7. The Commission shall, where necessary and based on aproposal prepared by the Agency, update every six months themarketing authorisation which has been granted pursuant toArticle 10 or Article 32 of Regulation (EEC) No 2309/93.


The Community Register of Medicinal Products provided forin Articles 12 and 34 of Regulation (EEC) No 2309/93 shallbe updated as necessary.

8. Where the Agency is of the opinion that the notificationcannot be accepted, it shall, within the period referred to inparagraph 6, inform the holder who has submitted thenotification, stating the grounds on which its opinion is based.

9. Within 30 days of receipt of the opinion referred to inparagraph 8, the holder may amend the notification in orderto take due account of the grounds set out in the opinion. Inthat case the provisions of paragraphs 6 and 7 shall apply tothe amended notification.

10. If the holder does not amend the notification, thenotification shall be deemed to have been rejected. The Agencyshall inform the holder accordingly.

Article 6

Approval procedure for major variations type II

1. With regard to major variations of type II, the holdershall submit to the Agency an application accompanied by:

(a) the relevant particulars and supporting documentsreferred to in Article 3(1);

(b) the supporting data relating to the variation applied for;

(c) all documents amended as a result of the application;


(d) an addendum to or update of existing expert reports/overviews/summaries to take account of the variationapplied for;

(e) the relevant fee provided for in Regulation (EC) No 297/95.

2. An application shall only concern one type II variation.Where several type II variations are to be made to a singlemarketing authorisation, a separate application shall be sub-mitted in respect of each variation sought; each such appli-cation shall also contain a reference to the other applications.

3. By way of derogation to paragraph 2, where a type IIvariation leads to consequential variations, a single applicationmay cover all such consequential variations. The single appli-cation shall contain a description of the relation between theseconsequential variations.


5. If the application fulfils the requirements set out inparagraphs 1 to 4, the Agency shall acknowledge receipt of avalid application and shall start the procedure set out inparagraphs 6 to 11.

6. The competent Committee of the Agency shall give itsopinion within 60 days from the start of the procedure.

This period can be reduced having regard to the urgency ofthe matter, particularly for safety issues.

This period can be extended to 90 days for variationsconcerning changes to or addition of the therapeutic indi-cations.

This period will be extended to 90 days for variationsconcerning a change to or addition of a non-food-producingtarget species.

7. Within the periods laid down in paragraph 6, thecompetent Committee may send the holder a request forsupplementary information within a time limit set by thatCommittee. The procedure shall be suspended until such timeas the supplementary information has been provided. In thiscase the periods laid down in paragraph 6 may be extendedfor a further period to be determined by that Committee.

8. Where the competent Committee delivers an opinion,the Agency shall inform the holder and the Commissionforthwith and shall send to the Commission, where appropri-ate, the amendments to be made to the terms of the marketingauthorisation accompanied by the documents set out inArticle 9(3) and 31(3) of Regulation (EEC) No 2309/93.

9. Article 9(1) and (2) or Article 31(1) and (2) of Regulation(EEC) No 2309/93 shall apply to the opinion adopted by thecompetent Committee.

10. The Commission shall, where necessary and based onthe proposal prepared by the Agency, amend the marketingauthorisation that has been granted pursuant to Article 10 orArticle 32 of the Regulation (EEC) No 2309/93.

Decisions concerning variations related to safety issues shallbe implemented within a time-frame as agreed between theCommission and the holder.

The amended marketing authorisation shall be notified by theCommission to the holder.

11. The Community Register of Medicinal Products pro-vided for in Articles 12 and 34 of Regulation (EEC) No 2309/93 shall be updated as necessary.

Article 7

Human influenza vaccines

1. With regard to variations to the terms of the marketingauthorisations for human influenza vaccines, the procedureset out in paragraphs 2 to 6 shall apply.

2. Within 45 days following the date of the receipt of avalid application, the Agency shall give its opinion on thequality documents referred to in Module 3 of Annex I toDirective 2001/83/EC, based on an assessment report.

3. Within the period laid down in paragraph 2, the Agencymay request the holder to provide supplementary information.

4. The Agency shall address forthwith its opinion to theCommission.

The Commission shall adopt a decision updating the marketingauthorisation that has been granted pursuant to Article 10 ofthe Regulation (EEC) No 2309/93.

This decision shall be implemented on condition that the finalopinion of the Agency as provided for in paragraph 5 isfavourable.



5. The clinical data and, where appropriate, those concern-ing the stability of the medicinal product shall be addressed bythe holder to the Agency at the latest 12 days following theend of the time limit laid down in paragraph 2.

The Agency shall evaluate these data and shall give its finalopinion within 10 days of the reception of the data referred toin the first subparagraph. The Agency shall address the finalopinion to the Commission and to the marketing authorisationholder within the three following days.

6. The Community Register of Medicinal Products providedfor in Article 12 of Regulation (EEC) No 2309/93 shall beupdated as necessary.

Article 8

Pandemic situation with respect to human diseases

In case of a pandemic situation with respect to the humaninfluenza virus, duly recognised by the World Health Organis-ation or by the Community in the framework of Decision2119/98/EC of the European Parliament and of the Council (1),the Commission may exceptionally and temporarily considerthe variation to the terms of the market authorisation forhuman influenza vaccines to be accepted after an applicationhas been received and before the end of the procedure laiddown in Article 7. Nevertheless, complete clinical safety andefficacy data can be submitted during this procedure.

In case of a pandemic situation with respect to human diseasesother than the human influenza virus, the first paragraph andArticle 7 may be applied mutatis mutandis.

Article 9

Urgent safety restrictions

1. If the holder in the event of risk to public or animalhealth takes urgent safety restrictions, he/she shall forthwithinform the Agency thereof. If the Agency has not raisedany objections within 24 hours following receipt of thatinformation, the urgent safety restrictions shall be deemed asaccepted.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 3 June 2003.

For the Commission

Erkki LIIKANEN

Member of the Commission

(1) OJ L 268, 3.10.1998, p. 1.

The urgent safety restrictions shall be implemented within atime-frame, as agreed with the Agency.

The corresponding variation application reflecting the urgentsafety restrictions shall be submitted immediately and in anycase no later than 15 days after the initiation of the urgentsafety restrictions to the Agency for the application of theprocedures set out in Article 6.

2. Where the Commission imposes urgent safety restric-tions on the holder, the holder shall be obliged to submit anapplication for a variation taking account of the safetyrestrictions imposed by the Commission.

The urgent safety restrictions shall be implemented within atime-frame, as agreed with the Agency.

For the application of the procedures set out in Article 6, thecorresponding variation application reflecting the urgent safetyrestrictions, including appropriate documentation in supportof the change, shall be submitted to the Agency immediatelyand in any case no later than 15 days after the initiation of theurgent safety restrictions.

The first and second subparagraphs are without prejudice toArticles 18 and 40 of Regulation (EEC) No 2309/93.

Article 10

Repeal

Regulation (EC) No 542/95 is repealed.

References made to the repealed Regulation shall be construedas references to this Regulation.

Article 11

This Regulation shall enter into force on the 20th dayfollowing its publication in the Official Journal of the EuropeanUnion.

It shall apply from 1 October 2003. However, as regards theexamination of applications of variations to the terms ofplasma master files and of vaccine antigen master files, thisRegulation shall apply from the date of entry into force of theCommission Directive amending Annex I of Directive 2001/83/EC.


ANNEX I

LIST AND CONDITIONS FOR MINOR VARIATIONS (TYPES IA AND IB) TO A MARKETING AUTHORIS-ATION AS REFERRED TO IN ARTICLES 3 TO 5

Introductory statements

The titles of the variations are numbered and subcategories depicted by letters and numbers in smaller font. Theconditions necessary for a given variation to follow either a type IA or a type IB procedure are outlined for eachsubcategory and listed below each variation.

To cover any other changes, it is necessary to submit applications for any consequential or parallel variations, whichmay be linked to the change applied for, at the same time and to clearly describe the relation between these variations.

For notifications including a certificate of suitability from the European pharmacopoeia and when the variationconcerns the dossier submitted for the certificate, the documentation required for this change is to be submitted tothe European Directorate for the Quality of Medicines (EDQM). If the certificate is revised following evaluation ofthis change, any marketing authorisation concerned must be updated. In many cases this can be done through atype IA notification.

A biological medicinal product is a product, the active substance of which is a biological substance. A biologicalsubstance is a substance that is produced by or extracted from a biological source and for which a combination ofphysico-chemical-biological testing and the production process and its control is needed for its characterisation andthe determination of its quality.

As a result, the following shall be considered as biological medicinal products: immunological medicinal productsand medicinal products derived from human blood and human plasma as defined in Article 1(4) and (10) of Directive2001/83/EC, respectively; immunological veterinary medicinal products as defined in Article 1(7) of Directive 2001/82/EC; medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93; advancedtherapy medicinal products as defined in Part IV of Annex I to Directive 2001/83/EC.

A change in the manufacturing process of a non-proteinaceous component due to a subsequent introduction of abiotechnology step can be made in accordance with the provisions of variations type I No 15 or No 21, asappropriate. This specific variation is without prejudice to other variations listed in this Annex which can be appliedin this particular context. Introduction of a proteinaceous component obtained through a biotechnology processlisted in Part A of the Annex to Council Regulation (EEC) No 2309/93 in a medicinal product fall within the scopeof said Regulation. Community legislation applicable to specific groups of products (1) shall be complied with.

There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or anational pharmacopoeia of a Member State in the case that compliance with the updated monograph is implementedwithin six months of its publication and reference is made to the ‘current edition’ in the dossier of an authorisedmedicinal product.

For the purposes of this document, ‘test procedure’ has the same meaning as ‘analytical procedure’ and ‘limits’ havethe same meaning as ‘acceptance criteria’.

The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publishdetailed guidance on the documentation to be submitted.

(1) Food and food ingredients compliant with Regulation (EC) No 258/97 of the European Parliament and the Council (OJ L 43,14.2.1997, p. 1), colours for use in foodstuffs within the scope of Council Directive 94/36/EEC (OJ L 237, 10.9.1994, p. 13),food additives within the scope of Council Directive 88/388/EEC (OJ L 184, 15.7.1988, p. 61), extraction solvents within themeaning of Council Directive 88/344/EEC (OJ L 157, 24.6.1988, p. 28) as last amended by Directive 92/115/EEC (OJ L 409,31.12.1992, p. 31) and foods or food ingredients derived from a biotechnology step which has been introduced in themanufacturing/production are not required to be notified as a variation to the terms of the marketing authorisation.


Title of variation/conditions to be fulfilled Type

1. IAChange in the name and/or address of the marketing authorisation holder

Conditions:

The marketing authorisation holder shall remain the same legal entity.

2. IBChange in the name of the medicinal product

Conditions:

1. No confusion with the names of existing medicinal products or with the international non-proprietaryname (INN).

2. The check by the EMEA on the acceptability of the new name by the Member States should be finalisedbefore the variation application is submitted.

3. The change does not concern the addition of a name.

3. IAChange in the name of the active substance

Conditions:

The active substance shall remain the same.

4. IAChange in the name and/or address of a manufacturer of the active substance where no EuropeanPharmacopoeia certificate of suitability is available

Conditions:

The manufacturing site shall remain the same.

5. IAChange in the name and/or address of a manufacturer of the finished product

Conditions:

The manufacturing site shall remain the same.

6. Change in ATC Code

(a) Medicinal products for human use IA

Conditions:

Change following granting of or amendment to ATC Code by WHO.

(b) Veterinary medicinal products IA

Conditions:

Change following granting of or amendment to ATC Vet Code.

7. Replacement or addition of a manufacturing site for part or all of the manufacturing process of thefinished product

(a) Secondary packaging for all types of pharmaceutical Conditions: 1, 2 (see below) IAforms

(b) Primary packaging site

1. Solid pharmaceutical forms, e.g. tablets and cap- Conditions: 1, 2, 3, 5 IAsules

2. Semi-solid or liquid pharmaceutical forms Conditions: 1, 2, 3, 5 IB

3. Liquid pharmaceutical forms (suspensions, emul- Conditions: 1, 2, 3, 4, 5 IBsions)

(c) All other manufacturing operations except batch release Conditions: 1, 2, 4, 5 IB



Conditions:

1. Satisfactory inspection in the last three years by an inspection service of one of the Member States of theEEA or of a country where an operational good manufacturing practice (GMP) mutual recognitionagreement (MRA) exists between the country concerned and the EU.

2. Site appropriately authorised (to manufacture the pharmaceutical form or product concerned).

3. Product concerned is not a sterile product.

4. Validation scheme is available or validation of the manufacture at the new site has been successfullycarried out according to the current protocol with at least three production scale batches.

5. Product concerned is not a biological medicinal product.

8. Change in batch release arrangements and quality control testing of the finished product

(a) Replacement or addition of a site where batch control/ Conditions: 2, 3, 4 (see below) IAtesting takes place

(b) Replacement or addition of a manufacturer responsiblefor batch release

1. Not including batch control/testing Conditions: 1, 2 IA

2. Including batch control/testing Conditions: 1, 2, 3, 4 IA

Conditions:

1. The manufacturer responsible for batch release must be located within the EEA.

2. The site is appropriately authorised.

3. The product is not a biological medicinal product.

4. Method transfer from the old to the new site or new test laboratory has been successfully completed.

9. IADeletion of any manufacturing site (including for an active substance, intermediate or finishedproduct, packaging site, manufacturer responsible for batch release and site where batch controltakes place)

Conditions:

None

10. IBMinor change in the manufacturing process of the active substance

Conditions:

1. No change in qualitative and quantitative impurity profile or in physico-chemical properties.

2. The active substance is not a biological substance.

3. The synthetic route remains the same, i.e. intermediates remain the same. In the case of herbal medicinalproducts, the geographical source, production of the herbal substance and the manufacturing routeremain the same.



11. Change in batch size of active substance or intermediate

(a) Up to 10-fold compared to the original batch size Conditions: 1, 2, 3, 4 (see below) IAapproved at the grant of the marketing authorisation

(b) Downscaling Conditions: 1, 2, 3, 4, 5 IA

(c) More than 10-fold compared to the original batch size Conditions: 1, 2, 3, 4 IBapproved at the grant of the marketing authorisation

Conditions:

1. Any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment.

2. Test results of at least two batches according to the specifications should be available for the proposedbatch size.


4. The change does not affect the reproducibility of the process.

5. The change should not be the result of unexpected events arising during manufacture or because ofstability concerns.

12. Change in the specification of an active substance or a starting material/intermediate/reagent usedin the manufacturing process of the active substance

(a) Tightening of specification limits Conditions: 1, 2, 3 (see below) IA

Conditions: 2, 3 IB

(b) Addition of a new test parameter to the specificationof

1. an active substance Conditions: 2, 4, 5 IB

2. a starting material/intermediate/ reagent used in Conditions: 2, 4 IBthe manufacturing process of the active substance

Conditions:

1. The change is not a consequence of any commitment from previous assessments to review specificationlimits (e.g. made during the procedure for the marketing authorisation application or a type II variationprocedure).

2. The change should not be the result of unexpected events arising during manufacture.

3. Any change should be within the range of currently approved limits.

4. Any new test method does not concern a novel non-standard technique or a standard technique used ina novel way.


13. Change in test procedure for active substance or starting material, intermediate, or reagent used inthe manufacturing process of the active substance

(a) Minor change to an approved test procedure Conditions: 1, 2, 3, 5 (see below) IA

(b) Other changes to a test procedure, including replace- Conditions: 2, 3, 4, 5 IBment or addition of a test procedure



Conditions:

1. The method of analysis should remain the same (e.g. a change in column length or temperature, but nota different type of column or method); no new impurities are detected.

2. Appropriate (re-)validation studies have been performed in accordance with relevant guidelines.

3. Results of method validation show new test procedure to be at least equivalent to the former procedure.


5. The active substance, starting material, intermediate or reagent is not a biological substance.

14. Change in the manufacturer of the active substance or starting material/reagent/intermediate in themanufacturing process of the active substance where no European Pharmacopoeia certificate ofsuitability is available

(a) Change in site of the already approved manufacturer Conditions: 1, 2, 4 (see below) IB(replacement or addition)

(b) New manufacturer (replacement or addition) Conditions: 1, 2, 3, 4 IB

Conditions:

1. The specifications (including in-process controls, methods of analysis of all materials), method ofpreparation (including batch size) and detailed route of synthesis are identical to those already approved.

2. Where materials of human or animal origin are used in the process, the manufacturer does not use anynew supplier for which assessment is required of viral safety or of compliance with the current Note forGuidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human andVeterinary Medicinal Products.

3. The current or new active substance manufacturer does not use a drug master file.

4. The change does not concern a medicinal product containing a biological active substance.

15. Submission of a new or updated European Pharmacopoeia certificate of suitability for an activesubstance or starting material/reagent/intermediate in the manufacturing process of the activesubstance

(a) From a manufacturer currently approved Conditions: 1, 2, 4 (see below) IA

(b) From a new manufacturer (replacement or addition)

1. Sterile substance Conditions: 1, 2, 3, 4 IB

2. Other substances Conditions: 1, 2, 3, 4 IA

(c) Substance in veterinary medicinal product for use in Conditions: 1, 2, 3, 4 IBanimal species susceptible to TSE

Conditions:

1. The finished product release and end of shelf life specifications remain the same.

2. Unchanged additional (to European Pharmacopoeia) specifications for impurities and product specificrequirements (e.g. particle size profiles, polymorphic form), if applicable.

3. The active substance will be tested immediately prior to use if no retest period is included in the EuropeanPharmacopoeia certificate of suitability, or if data to support a retest period is not provided.

4. The manufacturing process of the active substance, starting material/reagent/intermediate does notinclude the use of materials of human or animal origin for which an assessment of viral safety data isrequired.



16. Submission of a new or updated TSE European Pharmacopoeia certificate of suitability for anactive substance or starting material/reagent/intermediate in the manufacturing process of theactive substance for a currently approved manufacturer and currently approved manufacturingprocess

(a) Substance in veterinary medicinal product for use in Conditions: None IBanimal species susceptible to TSE

(b) Other substances Conditions: None IA

17. Change in:

(a) the re-test period of the active substance Conditions: 1, 2, 3 (see below) IB

(b) the storage conditions for the active substance Conditions: 1, 2 IB

Conditions:

1. Stability studies have been done according to the currently approved protocol. The studies must showthat the agreed relevant specifications are still met.



18. IBReplacement of an excipient with a comparable excipient

Conditions:

1. Same functional characteristics of the excipient.

2. The dissolution profile of the new product determined on a minimum of two pilot scale batches iscomparable to the old one (no significant differences regarding comparability cf Note for Guidance onBio-availability and Bio-equivalence, Annex II; the principles contained in this note for guidance formedicinal products for human use should still be taken into account for veterinary medicinal products, ifrelevant). For herbal medicinal products where dissolution testing may not be feasible, the disintegrationtime of the new product is comparable to the old one.

3. Any new excipient does not include the use of materials of human or animal origin for which assessmentis required of viral safety data. For excipients in a veterinary medicinal product for use in animal speciessusceptible to TSE, a risk assessment has been carried out by the competent authority.

4. It does not concern a medicinal product containing a biological active substance.

5. Stability studies in accordance with the relevant guidelines have been started with at least two pilot scaleor industrial scale batches and at least three months’ satisfactory stability data are at the disposal of theapplicant and assurance that these studies will be finalised. Data will be provided immediately to thecompetent authorities if outside specifications or potentially outside specifications at the end of theapproved shelf life (with proposed action).

19. Change in specification of an excipient


Conditions: 2, 3 IB

(b) Addition of a new test parameter to the specification Conditions: 2, 4, 5 IB



Conditions:

1. The change is not a consequence of any commitment from previous assessments (e.g. made during theprocedure for the marketing authorisation application or a type II variation procedure).




5. The change does not concern adjuvant for vaccines or a biological excipient.

20. Change in test procedure for an excipient

(a) Minor change to an approved test procedure Conditions: 1, 2, 3, 5 (see below) IA

(b) Minor change to an approved test procedure for a Conditions: 1, 2, 3 IBbiological excipient

(c) Other changes to a test procedure, including replace- Conditions: 2, 3, 4, 5 IBment of an approved test procedure by a new testprocedure

Conditions:

1. The method of analysis should remain the same (e.g. a change in column length or temperature, but nota different type of column or method); no new impurities are detected.




5. The substance is not a biological excipient.

21. Submission of a new or updated European Pharmacopoeia certificate of suitability for an excipient

(a) From a manufacturer currently approved Conditions: 1, 2, 3 (see below) IA

(b) From a new manufacturer (replacement or addition)

1. Sterile substance Conditions: 1, 2, 3 IB

2. Other substances Conditions: 1, 2, 3 IA

(c) Substance in veterinary medicinal product for use in Conditions: 1, 2, 3 IBanimal species susceptible to TSE

Conditions:

1. The finished product release and end of shelf-life specifications remain the same.

2. Unchanged additional (to European Pharmacopoeia) specifications for product specific requirements (e.g.particle size profiles, polymorphic form), if applicable.

3. The manufacturing process of the excipient does not include the use of materials of human or animalorigin for which an assessment of viral safety data is required.



22. Submission of a new or updated TSE European Pharmacopoeia certificate of suitability for anexcipient

(a) From a manufacturer currently approved or a new Conditions: None IAmanufacturer (replacement or addition)

(b) Excipient in veterinary medicinal product for use in Conditions: None IBanimal species susceptible to TSE

23. Change in source of an excipient or reagent from a TSE risk to a vegetable or synthetic material

(a) Excipient or reagent used in manufacture of biological Conditions: (see below) IBactive substance or manufacture of a finished productcontaining biological active substance

(b) Other cases Conditions: (see below) IA

Conditions:

Excipient and finished product release and end of shelf-life specifications remain the same.

24. IBChange in synthesis or recovery of a non-pharmacopoeial excipient (when described in the dossier)

Conditions:

1. Specifications are not adversely affected; no change in qualitative and quantitative impurity profile or inphysico-chemical properties.

2. The excipient is not a biological substance.

25. Change to comply with European Pharmacopoeia or with the national pharmacopoeia of a MemberState

(a) Change of specification(s) of a former non-Europeanpharmacopoeial substance to comply with EuropeanPharmacopoeia or with the national pharmacopoeia ofa Member State

1. Active substance Conditions: 1, 2 (see below) IB

2. Excipient Conditions: 1, 2 IB

(b) Change to comply with an update of the relevantmonograph of the European Pharmacopoeia ornational pharmacopoeia of a Member State

1. Active substance Conditions: 1, 2 IA

2. Excipient Conditions: 1, 2 IA

Conditions:

1. The change is made exclusively to comply with the pharmacopoeia.

2. Unchanged specifications (additional to the pharmacopoeia) for product specific properties (e.g. particlesize profiles, polymorphic form), if applicable.



26. Change in the specifications of the immediate packaging of the finished product


Conditions: 2, 3 IB

(b) Addition of a new test parameter Conditions: 2, 4 IB

Conditions:





27. Change to a test procedure of the immediate packaging of the finished product

(a) Minor change to an approved test procedure Conditions: 1, 2, 3 (see below) IA

(b) Other changes to a test procedure, including replace- Conditions: 2, 3, 4 IBment or addition of a test procedure

Conditions:

1. The method of analysis should remain the same (e.g. a change in column length or temperature, but nota different type of column or method).

2. Appropriate (re-)validation studies were performed in accordance with relevant guidelines.



28. IAChange in any part of the (primary) packaging material not in contact with the finished productformulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield(different plastic used))

Conditions:

The change does not concern a fundamental part of the packaging material, which affects the delivery, use,safety or stability of the finished product.

29. Change in the qualitative and/or quantitative composition of the immediate packaging material

(a) Semi-solid and liquid pharmaceutical forms Conditions: 1, 2, 3, 4 (see below) IB

(b) All other pharmaceutical forms Conditions: 1, 2, 3, 4 IA

Conditions: 1, 3, 4 IB



Conditions:

1. The product concerned is not a biological or sterile product.

2. The change only concerns the same packaging type and material (e.g. blister to blister).

3. The proposed packaging material must be at least equivalent to the approved material in respect of itsrelevant properties.

4. Relevant stability studies in accordance with the relevant guidelines have been started with at least twopilot scale or industrial scale batches and at least three months’ stability data are at the disposal of theapplicant. Assurance is given that these studies will be finalised and that the data will be providedimmediately to the competent authorities if outside specifications or potentially outside specifications atthe end of the approved shelf life (with proposed action).

30. Change (replacement, addition or deletion) in supplier of packaging components or devices (whenmentioned in the dossier); spacer devices for metered dose inhalers are excluded

(a) Deletion of a supplier Conditions: 1 (see below) IA

(b) Replacement or addition of a supplier Conditions: 1, 2, 3, 4 IB

Conditions:

1. No deletion of packaging component or device.

2. The qualitative and quantitative composition of the packaging components/device remains the same.

3. The specifications and quality control method are at least equivalent.

4. The sterilisation method and conditions remain the same, if applicable.

31. Change to in-process tests or limits applied during the manufacture of the product

(a) Tightening of in-process limits Conditions: 1, 2, 3 (see below) IA

Conditions: 2, 3 IB

(b) Addition of new tests and limits Conditions: 2, 4 IB

Conditions:

1. The change is not a consequence of any commitment from previous assessments (e.g. made during theprocedure for the marketing authorisation application or a type II variation procedure).


3. Any change should be within the range of the currently approved limits.


32. Change in batch size of the finished product

(a) Up to 10-fold compared to the original batch size Conditions: 1, 2, 3, 4, 5 (see IAapproved at the grant of the marketing authorisation below)

(b) Downscaling down to 10-fold Conditions: 1, 2, 3, 4, 5, 6 IA

(c) Other situations Conditions: 1, 2, 3, 4, 5, 6, 7 IB



Conditions:

1. The change does not affect the reproducibility and/or consistency of the product.

2. The change relates only to standard immediate release oral pharmaceutical forms and to non-sterile liquidforms.

3. Any changes to the manufacturing method and/or to the in-process controls are only those necessitatedby the change in batch size, e.g. use of different-sized equipment.

4. Validation scheme is available or validation of the manufacture has been successfully carried out accordingto the current protocol with at least three batches at the proposed new batch size in accordance with therelevant guidelines.

5. It does not concern a medicinal product containing a biological active substance.

6. The change should not be a result of unexpected events arisen during manufacture or because of stabilityconcerns.

7. Relevant stability studies in accordance with the relevant guidelines have been started with at least onepilot scale or industrial scale batch and at least three months’ stability data are at the disposal of theapplicant. Assurance is given that these studies will be finalised and that the data will be providedimmediately to the competent authorities if outside specifications or potentially outside specifications atthe end of the approved shelf life (with proposed action).

33. IBMinor change in the manufacture of the finished product

Conditions:

1. The overall manufacturing principle remains the same.

2. The new process must lead to an identical product regarding all aspects of quality, safety and efficacy.

3. The medicinal product does not contain a biological active substance.

4. In case of a change in the sterilisation process, the change is to a standard pharmacopoeial cycle only.

5. Relevant stability studies in accordance with the relevant guidelines have been started with at least onepilot scale or industrial scale batch and at least three months’ stability data are at the disposal of theapplicant. Assurance is given that these studies will be finalised and that the data will be providedimmediately to the competent authorities if outside specifications or potentially outside specifications atthe end of the approved shelf life (with proposed action).

34. Change in the colouring system or the flavouring system currently used in the finished product

(a) Reduction or deletion of one or more components ofthe

1. colouring system Conditions: 1, 2, 3, 4, 7 (see IAbelow)

2. flavouring system Conditions: 1, 2, 3, 4, 7 IA

(b) Increase, addition or replacement of one or morecomponents of

1. colouring system Conditions: 1, 2, 3, 4, 5, 6, 7 IB

2. flavouring system Conditions: 1, 2, 3, 4, 5, 6, 7 IB

Conditions:

1. No change in functional characteristics of the pharmaceutical form e.g. disintegration time, dissolutionprofile.

2. Any minor adjustment to the formulation to maintain the total weight should be made by an excipientwhich currently makes up a major part of the finished product formulation.

3. The finished product specification has only been updated in respect of appearance/odour/taste and ifrelevant, deletion or addition of an identification test.



4. Stability studies (long-term and accelerated) in accordance with relevant guidelines have been started withat least two pilot scale or industrial batches and at least three months’ satisfactory stability data are at thedisposal of the applicant and assurance that these studies will be finalised. Data shall be providedimmediately to the competent authorities if outside specifications or potentially outside specifications atthe end of the approved shelf life (with proposed action). In addition, where relevant, photo-stabilitytesting should be performed.

5. Any new components must comply with the relevant Directives (e.g. Council Directive 78/25/EEC (OJL 229, 15.8.1978, p. 63) as amended for colorants and Directive 88/388/EEC for flavours).

6. Any new component does not include the use of materials of human or animal origin fir whichassessment is required of viral safety data or compliance with the current Note for Guidance onMinimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human andVeterinary Medicinal Products.

7. Biological veterinary medicinal products for oral use for which the colouring or flavouring agent isimportant for the uptake by the target animal species are excluded.

35. Change in coating weight of tablets or change in weight of capsule shells

(a) Immediate release oral pharmaceutical forms Conditions: 1, 3, 4 (see below) IA

(b) Gastro-resistant, modified or prolonged release phar- Conditions: 1, 2, 3, 4 IBmaceutical forms

Conditions:

1. The dissolution profile of the new product, determined on a minimum of two pilot scale batches, iscomparable to the old one. For herbal medicinal products where dissolution testing may not be feasible,the disintegration time of the new product is comparable to the old one.

2. The coating is not a critical factor for the release mechanism.

3. The finished product specification has only been updated in respect of weight and dimensions, ifapplicable.

4. Stability studies in accordance with the relevant guidelines have been started with at least two pilot scaleor industrial scale batches and at least three months’ satisfactory stability data are at the disposal of theapplicant and assurance that these studies will be finalised. Data will be provided immediately to thecompetent authorities if outside specifications or potentially outside specifications at the end of theapproved shelf life (with proposed action).

36. Change in shape or dimensions of the container or closure

(a) Sterile pharmaceutical forms and biological medicinal Conditions: 1, 2, 3 (see below) IBproducts

(b) Other pharmaceutical forms Conditions: 1, 2, 3 IA

Conditions:

1. No change in qualitative or quantitative composition of the container.

2. The change does not concern a fundamental part of the packaging material, which affect the delivery,use, safety or stability of the finished product.

3. In case of a change in the head space or a change in the surface/volume ratio, stability studies inaccordance with the relevant guidelines have been started with at least two pilot scale (three for biologicalmedicinal products) or industrial scale batches and at least three months’ (six months for biologicalmedicinal products) stability data are at the disposal of the applicant. Assurance is given that these studieswill be finalised and that the data will be provided immediately to the competent authorities if outsidespecifications or potentially outside specifications at the end of the approved shelf life (with proposedaction).



37. Change in the specification of the finished product

(a) Tightening of specification limits Conditions: 1, 2, 3 (See below) IA

Conditions: 2, 3 IB

(b) Addition of a new test parameter Conditions: 2, 4, 5 IB

Conditions:





5. The test procedure does not apply to a biological active substance or biological excipient in the medicinalproduct.

38. Change in test procedure of the finished product

(a) Minor change to an approved test procedure Conditions: 1, 2, 3, 4, 5 (see IAbelow)

(b) Minor change to an approved test procedure for Conditions: 1, 2, 3, 4 IBbiological active substance or biological excipient

(c) Other changes to a test procedure, including replace- Conditions: 2, 3, 4, 5 IBment or addition of a test procedure

Conditions:

1. The method of analysis should remain the same (e.g. a change in column length or temperature, but nota different type of column or method).




5. The test procedure does not apply to a biological active substance or biological excipient in the medicinalproduct.

39. IAChange or addition of imprints, bossing or other markings (except scoring/break lines) on tabletsor printing on capsules, including replacement, or addition of inks used for product marking

Conditions:

1. Finished product release and end of shelf-life specifications have not been changed (except for appearance).

2. Any new ink must comply with the relevant pharmaceutical legislation.



40. Change of dimensions of tablets, capsules, suppositories or pessaries without change in qualitativeor quantitative composition and mean mass

(a) Gastro-resistant, modified or prolonged release phar- Conditions: 1, 2 (see below) IBmaceutical forms and scored tablets

(b) All other tablets, capsules, suppositories and pessaries Conditions: 1, 2 IA

Conditions:

1. The dissolution profile of the reformulated product is comparable to the old one. For herbal medicinalproducts, where dissolution testing may not be feasible, the disintegration time of the new productcompared to the old one.

2. Release and end of shelf-life specifications of the product have not been changed (except for dimensions).

41. Change in pack size of the finished product

(a) Change in the number of units (e.g. tablets, ampoules,etc.) in a pack

1. Change within the range of the currently approved Conditions: 1, 2 (see below) IApack sizes

2. Change outside the range of the currently Conditions: 1, 2 IBapproved pack sizes

(b) Change in the fill weight/fill volume of non-parenteral Conditions: 1, 2 IBmulti-dose products

Conditions:

1. New pack size should be consistent with the posology and treatment duration as approved in thesummary of product characteristics.

2. The primary packaging material remains the same.

42. Change in:

(a) the shelf life of the finished product

1. As packaged for sale Conditions: 1, 2, 3 (see below) IB

2. After first opening Conditions: 1, 2 IB

3. After dilution or reconstitution Conditions: 1, 2 IB

(b) the storage conditions of the finished product or the Conditions: 1, 2, 4 IBdiluted/reconstituted product

Conditions:

1. Stability studies have been done according to the currently approved protocol. The studies must showthat the agreed relevant specifications are still met.


3. The shelf life does not exceed five years.

4. The product is not a biological medicinal product.



43. Addition, replacement or deletion of a measuring or administration device not being an integratedpart of the primary packaging (spacer devices for metered dose inhalers are excluded)

(a) Medicinal products for human use

1. Addition or replacement Conditions: 1, 2 (see below) IA

2. Deletion Conditions: 3 IB

(b) Veterinary medicinal products Conditions: 1, 2 IB

Conditions:

1. The proposed measuring device must accurately deliver the required dose for the product concerned inline with the approved posology and the results of such studies should be available.

2. The new device is compatible with the medicinal product.

3. The medicinal product can still be accurately delivered.

44. Change in specification of a measuring device or administration device for veterinary medicinalproducts


Conditions: 2, 3 IB

(b) Addition of a new test parameter Conditions: 2, 4 IB

Conditions:





45. Change in test procedure of a measuring or administration device for veterinary medicinal products

(a) Minor change to an approved test procedure Conditions: 1, 2, 3 (see below) IA

(b) Other changes to a test procedure, including replace- Conditions: 2, 3, 4 IBment of approved test procedure by new test procedure

Conditions:

1. The new or updated procedure is demonstrated to be at least equivalent to the former test procedure.

2. Appropriate (re-)validation studies have been performed in accordance with the relevant guidelines.





46. IBChange in the summary of product characteristics, labelling and package leaflet/insert as aconsequence of a final opinion in the context of a referral procedure in accordance with Articles 31and 32 of Directive 2001/83/EC or Articles 35 and 36 of Directive 2001/82/EC

Conditions:

The variation only concerns the introduction of changes to the summary of product characteristics, labellingand package leaflet/insert in order to take account of a scientific opinion delivered in the context of a referral inaccordance with Articles 31 and 32 of Directive 2001/83/EC or Articles 35 and 36 of Directive 2001/82/EC.

47. Deletion of:

(a) a pharmaceutical form IA

(b) a strength IA

(c) a pack size(s) IA

Conditions:

The remaining product presentations(s) must be adequate for the dosing instructions and treatment duration asmentioned in the summary of product characteristics.


ANNEX II

CHANGES TO A MARKETING AUTHORISATION LEADING TO AN EXTENSION APPLICATION ASREFERRED TO IN ARTICLE 2

These changes, listed below, will be regarded as an ‘extension’ application as referred to in Article 2.

An extension to or a modification of the existing marketing authorisation will have to be granted by the Community.

The name of the medicinal product will be the same for the ‘extension’ as it is for the existing marketing authorisationof the medicinal product.

The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publishdetailed guidance on the documentation to be submitted.

Changes requiring an extension application

1. Changes to the active substance(s):

(i) replacement of the active substance(s) by a different salt/ester complex/derivative (with the sametherapeutic moiety) where the efficacy/safety characteristics are not significantly different,

(ii) replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g.racemate by a single enantiomer) where the efficacy/safety characteristics are not significantly different,

(iii) replacement of a biological substance or product of biotechnology with one of a slightly differentmolecular structure. Modification of the vector used to produce the antigen/source material, including anew master cell bank from a different source where the efficacy/safety characteristics are not significantlydifferent,

(iv) a new ligand or coupling mechanism for a radio-pharmaceutical,

(v) change to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy/safety characteristics are not significantly different.

2. Changes to strength, pharmaceutical form and route of administration:

(i) change of bio-availability;

(ii) change of pharmaco-kinetics e.g. change in rate of release,

(iii) change or addition of a new strength/potency,

(iv) change or addition of a new pharmaceutical form,

(v) change or addition of a new route of administration (1).

3. Other changes specific to veterinary medicinal products to be administered to food-producing animals:

Change or addition of target species.

(1) For parenteral administration, it is necessary to distinguish between intraarterial, intravenous, intramuscular, subcutaneous andother routes. For administration to poultry, respiratory, oral and ocular (nebulisation) routes used for vaccination are consideredto be equivalent routes of administration.

Documents

COMMISSION REGULATION (EC) No 1085/2003 of 3 …...Articles 15(4) and 37(4) thereof, Whereas: (1) In the light of practical experience in the application of Commission Regulation (EC)